Blood coagulation is a complex chemical and physical reaction that occurs when blood comes into contact with an activating agent, such as an activating surface or an activating agent. (In this context, the term “blood” means whole blood, citrated blood, platelet concentrate, plasma, or control mixtures of plasma and blood cells, unless otherwise specifically called out otherwise; the term particularly includes heparinized blood.)
Several tests of coagulation are routinely utilized to assess the complicated cascade of events leading to blood clot formation and test for the presence of abnormalities or inhibitors of this process. Among these tests are activated clotting time (ACT), which includes high range ACT (HRACT), a test which features a slope response to moderate to high heparin levels (up to 6 U/mL) in whole blood drawn from a patient during cardiac surgery. The ACT test formulated to respond to low heparin levels (0.1 to 1.0 U/mL) in whole blood drawn from a patient during the extracorporeal membrane oxygenation (ECMO) procedure is low range ACT (LRACT), which is also in the scope of this application.
Unfractionated heparin is most commonly used for anticoagulation during cardiac pulmonary bypass (CPB) surgery to prevent gross clotting of the bypass circuit and more activation and consumption of coagulation system components. While an ACT test responds to heparin, it is a global assessment of coagulation status of blood and affected by many other factors other than heparin, such as hemodilution and temperature. Due to the limitation of ACT monitoring and the variability of patient response to heparin dose, individualized heparin and protamine management based on heparin protamine titration test has associated with improved clinical outcomes. The heparin protamine titration test uses activated clotting time as test end point, which is also in the scope of this application.
During heart bypass surgery, the platelets of blood circulated in an extracorporeal circuit may become activated by contact with the materials present in the extracorporeal circuit. This activation may be reversible or irreversible. Once platelets are irreversibly activated, they lose their ability to function further. A deficiency of functional platelets in the blood may be indicative of an increased probability of a post-operative bleeding problem. Such a deficiency, and the resulting post-operative bleeding risk, could be remedied by a transfusion of platelet concentrate. Platelet functionality tests, which can use activated clotting time as a test end point, can identify a deficiency of platelets or functional platelets and aid the attending surgeon in ascertaining when to administer a platelet concentrate transfusion. Such a test is further useful in ascertaining the efficacy of a platelet transfusion. By performing the platelet functionality test following a platelet transfusion, it is possible to determine if additional platelet concentrate transfusions are indicated. Real-time assessment of clotting function at the operative site may be performed to evaluate the result of therapeutic interventions and also to test and optimize, a priori, the treatment choice and dosage.
Other anticoagulant drugs used in cardiac surgery and cardiac catheterization procedures, such as low molecular weight heparin and bivalirudin, are also monitored with activated clotting time. The clotting time test used to monitor bivalirudin uses ecarin as activator, thus the test is called ecarin time (ECT). This application works with all clot time based tests.
ACT tests described in this application are based on the viscosity change of a test sample within a test chamber. During a test cycle, a ferromagnetic washer immersed in the test sample is lifted to the top of the test chamber by magnetic force produced by a magnetic field located at the top of the test chamber; the washer is then held at the top of the test chamber for a specific time. After the specified holding time, the washer is then dropped through the test sample via gravity. The increased viscosity due to the clotting of the test sample slows the motion of the washer. Thus, if the time that the washer travels through a specified distance (i.e., the washer “drop time”) is greater than a preset value (the clot detection sensitivity threshold), a clot is detected and an ACT value is reported.
A particular apparatus and method for detecting changes in human blood viscosity based on this principle is disclosed in U.S. Pat. Nos. 5,629,209 and 6,613,286, in which heparinized blood is introduced into a test cartridge through an injection port and fills a blood receiving/dispensing reservoir. The blood then moves from the reservoir through at least one conduit into at least one blood-receiving chamber where it is subjected to a viscosity test. A freely movable ferromagnetic washer is also located within the blood-receiving chamber that is moved up using an electromagnet of the test apparatus and allowed to drop with the force of gravity. Changes in the viscosity of the blood that the ferromagnetic washer falls through are detected by determining the position of the ferromagnetic washer in the blood-receiving chamber in a given time, or by a given number of rises and falls of the ferromagnetic washer. Air in the conduit and blood-receiving chamber is vented to atmosphere through a further vent conduit and an air vent/fluid plug as the blood sample is fills the blood-receiving chamber.
The movement of the washer in the above approach is actively controlled only when it is moved up, and the washer passively drops with the force of gravity. The washer is free to float in the test chamber and may drift side-to-side as it is moved up or floats downward. The side-to-side drifting movement may affect the rise time and the fall time, which could add error to the coagulation time measured. The washer may eventually stop moving as a clot forms about it, and no additional information can be obtained on the coagulation process in the sample.